Effect of castration on the smooth muscle cells of the internal sex organs of the rat: influence of the smooth muscle on the sympathetic neurons innervating the vas deferens, seminal vesicle and coagulating gland. Wet weights of vas deferens, seminal vesicle and coagulating gland were reduced by almost 80 to 90% 10 weeks after castration. Endogenous norepinephrine content and dopamine-beta-hydroxylas activity of these tissues were also reduced to the same degree. One week after castration there was approximately a 50% loss in the weight of all three organs. However, this was accompanied by an equal reduction in norepinephrine content and dopamine-beta-hydroxylase activity only in the vas deferens. Two weeks later the degree of reductions in wet weight, norepinephrine content and dopamine-beta-hydroxylase activity was almost identical for all three organs. Treatment of 40-day castrate rats with testosterone (10 mg/kg s.c.) not only restored the wet weights of the internal sex organs to normal but their norepinephrine content and dopamine-beta-hydroxylase activity as well. Castration of immature rats (10-14 days old) resulted in retardation of growth of the vas deferens and seminal vesicle by 90-95%, and similar reductions in norepinephrin content and dopamine-beta-hydroxylase activity, when compared to the tissues of control littermates on the 90th postoperative day. Histological examination of normal and castrate rats indicated that, along with a reduction in epithelial cells, the smooth muscle cells of the vas deferens, seminal vesicle and coagulating gland was markedly reduce in size as well. Administration of testosterone completely reversed these changes. Furthermore, deoxyribonucleic acid content of the seminal vesicle and coagulating gland was reduced by 50% after castration and then restored to control level after testosterone treatment. Taken together, it seems that atrophy of the internal sex organs following castration is a combined effect of reduction in size and number of smooth muscle cells. Therefore, it is concluded that any alteration in the size of smooth muscle cells or loss of such cells of the internal sex organs indirectly influences their sympathetic nerves in such a manner that norepinephrine concentrations, and thereby the density of innervation, are maintained at normal levels.


Characterization by cyproheptadine of the dopamine-induced contraction in canine isolated arteries. Spirally cut strips of isolated canine femoral and carotid arteries were used to characterize the vasoconstrictor effect of dopamine. A serotonin antagonist, cyproheptadine, 10- minus 7, 3 X 10- minus 7 and 10-minus 6 M, inhibited dopamine (pA2 = 7.46 plus or minus 0.11), tryptamine (pA2 = 7.38 plus or minus 0.09) and serotonin-induced contractions (pA2 = 7.59 plus or minus 0.09). Cyproheptadine shifted the threshold concentration of dopamine 2 log units to the right without altering norepinephrine response. In protection experiments, preincubation with serotonin (10-minus 5 M) for 10 minutes protected serotonin and tryptamine receptors from cyproheptadine (3 X 10-minus 7 M) and phenoxybenzamine (10-minus 6 M) blockade. Serotonin cross-protected dopamine receptors also. Reciprocally dopamine (10-minus 4 M) protected its own receptors as well as those for serotonin and tryptamine. Norepinephrine did not afford any protection of dopamine, serotonin or tryptamine receptors but did protect its own receptors from phenoxybenzamine blockade. The attempt to characterize the receptor subserving dopamine-induced contraction failed to confirm a relationship between dopamine and alpha adrenoceptors. Since dopamine, tryptamine and serotonin, unlike norepinephrine, were sensitive to cyproheptadine blockade, dopamine-induced contraction appeared to be mediated by a receptor closely related to serotonin receptors. Therefore, alpha adrenoceptors may not be exclusively involved in the vasoconstriction evoked by dopamine on canine vasculature.


Pressure-dependent factors in edema formation in canine forelimbs. Acetycholine (10 mug/min) infused intra-arterially for 30 minutes into naturally perfused forelimbs increased forelimb weight 23 g. largely due to edema formation. The weight gain was associated with markedly elevated skin and skeletal muscle blood flows and small vein pressures, suggesting that the edema was attributable, in part, to a rise in microvascular pressures. Mechanically increasing venous pressure and blood flow to similar levels for 30 minutes in pump-perfused forelimbs produced a weight gain of 27 g. The rate of weight gain for the acetylcholine and mechanical alterations was nearly identical. Acetylcholine and mechanical alterations both increased forelimb lymph flow rate but failed to increase lymph total protein concentration significantly. These studies indicate that in the dog forelimb elevated microvascular pressures result in edema formation by increasing the transcapillary hydrostatic pressure gradient without producing an important decrease in the transcapillary colloid osmotic pressure gradient. Increased pressure is not associated with a large increase in microvascular permeability to plasma proteins as is seen with the administration of high doses of histamine and bradykinin.


Experimental evidence for calcium independent catecholamine secretion from the bovine adrenal medulla. The purpose of this investigation was to establish the existence of a calcium-independent mechanism for catecholamine secretion from the adrenal medulla. Concentration-effect curves were obtained using isolated perfused (5 ml/min; 25 degrees C) bovine adrenal medullae stimulated with acetaldehyde (1-64 mM). Catecholamine secretion was the same in presence and in absence of calcium in the perfusion medium and was not diminished by the addition of magnesium (5 X 10-minus 3 M) to the calcium-free medium. Stimulation of 45-Ca-labeled adrenals with 23 mM acetaldehyde evoked secretion of catecholamines but not 45-Ca. Furthermore, examination of the distribution of 45-Ca and catecholamines in subcellular fractions (cytosol, nuclei, microsomes, mitochondria and chromaffin granules) from acetaldehyde-stimulated and nonstimulated glands showed that acetaldehyde stimulation caused no mobilization of 45-Ca from any of the intracellular pools, but significantly decreased the catecholamine content of a chromaffin granule fraction with a concomitant increase of catecholamines in the cytosolic fraction. These results establish an adrenomedullary secretory mechanism independent of both extracellular and intracellular calcium and indicate that acetaldehyde evokes catecholamine secretion by this calcium-independent mechanism, releasing the intragranular hormones into the cytoplasm prior to their extrusion from the chromaffin cell.


The stereoisomers of 3,4-dihydroxyphenylserine as precursors of norepinephrine. The action of the four stereoisomers of 3,4-dihydroxyphenylserine (DOPS) on the monoamine content of brain and heart was investigated with biochemical and histochemical methods. The (+)-erythro-DOPS (50-250 mg/kg i.p.), due to its alphaS configuration, was readily decarboxylated in vivo leading to an accumulation of norepinephrine (NE) in brain and heart. The amino probably corresponded to the unnatural (+) form since the amino acid shows betaS configuration. The NE was located in brain regions rich in noradrenergic (hypothalamus, locus ceruleus), dopaminergic (neostriatum, substantia nigra) and 5-hydroxytryptaminergic (raph'e nuclei) neurons. In addition, (+)-erythro-DOPS decreased the level of endogenous 5-hydroxytryptamine and dopamine and increased that of 5-hydroxyindoleacetic and homovanillic acid in the brain indicating a displacement of 5-hydroxytryptamine and dopamine, respectively, from their storage sites. Inhibitors of extracerebral decarboxylase (benserazid and carbidopa) diminished the (+)-erythro-DOPS-induced increase in cerebral NE by inhibiting the decarboxylation of the amino acid in the walls of the brain capillaries. The (-)-threo-DOPS, which also show alphaS configuration, was decarboxylated too, leading to a rise in cardiac NE. The amine was likely to correspond to the natural(-)-isomer since (-)-threo-DOPS has betaR configuration. This increase in NE lasted much longer than that caused by (+)-erythro-DOPS. In the brain, the accumulation of NE was negligible after i.p. administration of (-)-threo-DOPS but marked after injection of the isomer into a cerebral ventricle indicating a poor penetration of (-)-threo-DOPS through the blood-brain barrier. High doses (500 and 1000 mg/kg i.p.) of (-)-erythro- and (+)-threo-DOPS caused only a slight increase in cerebral and cardiac NE since, due to their alphaR configuration, they were probably not decarboxylated to a major extent. In conclusion, (+)-NE formed from (+)-erythro-DOPS probably accumulates in the storage sites of the endogenous monoamines where it might function as a false neurotransmitter.


Blockade by reserpine of methylphenidate-induced release of brain dopamine. The cerebroventricular systems of cats were perfused by introducing artificial cerebrospinal fluid into a lateral ventricle and collecting the perfusate at the aqueduct. 3-H-tyrosine was continuously added to the perfusing cerebrospinal fluid and the perfusate was analyzed for 3-H-catecholamines. Intraventricular or intravenous administration of methylphenidate increased the efflux of 3-H-dopamine. In cats pretreated with reserpine, this response to methylphenidate was reduced while the efflux of 3-H-dopamine caused by delta-amphetamine was slightly increased. These results provide direct biochemical evidence in support of the hypothesis that the central stimulant action of amphetamine and methylphenidate result from their abilities to preferentially release dopamine from "newly synthesized" and "stored" pools, respectively.


A comparison of the effects of morphine and forced running upon the incorporation of 14-C-tyrosine into 14-C-catecholamines in mouse brain, heart and spleen. Morphine increases both the locomotor activity of mice and the incorporation of 14-C-tyrosine into 14-C-catecholamines in the mouse brain. To determine whether a relationship exists between increases in locomotor activity and increases in catecholamine synthesis, mice were treated with either morphine (100 mg/kg i.p.) or saline and were forced to run on a treadmill (5.4 m/min). When mice were given saline and forced to run, incorporation of 14-C-tyrosine into 14-C-catecholamines was increased over control values in the heart and spleen but unchanged in the brain. When mice were given morphine, but not forced to run, the incorporation of 14-C-tyrosine into 14-C-catecholamines was increased over control values in the brain but unchanged in the heart and spleen. Morphine decreased the catecholamine content of the mouse brain but not of the heart or spleen. Forced running did not change the catecholamine content of any tissue. The differences between the effects of morphine and forced increases in locomotor activity upon the incorporation of 14-C-tyrosine into 14-C-catecholamines and upon the catecholamine content in various tissues of the mouse indicate that the effects of morphine on catecholamine synthesis are not the result of changes in locomotor activity.


Isoproterenol- and epinephrine-induced changes in blood glucose and tissue glycogen levels in normal and diabetic rats: the influence of alteration in endogenous insulin levels and state of nourishment. The hyperglycemic activities of catecholamines vary drastically from one species to another. Within certain species, the activity of catecholamines is largely dependent upon the state of nourishment. In the rat, isoproterenol (ISO) produces significant hyperglycemia only in the fasted state whereas epinephrine (EPI) produces hyperglycemia in both the fed and the fasted states. In this study, measurement of plasma insulin and glucose levels in response to ISO and EPI showed that ISO produces dose-related increases in the insulin/glucose ratio and that the ratio is influenced greatly by the state of nourishment. On the other hand, EPI, an inhibitor of insulin release, reduced the insulin/glucose ratio. When a deficiency of insulin release was produced by alloxan treatment, the hyperglycemic activity of ISO was increased markedly whereas the activity of EPI did not change. Pretreatment of fed normal rats with ISO suppressed markedly the expected hyperglycemic response to a subsequent challenge with EPI. In contrast, injection of ISO prior to an EPI challenge in diabetic rats produced a hyperglycemic effect greater than that produced by either agent alone. These results suggest that insulin release by ISO regulates the hyperglycemic activity of this catecholamine in the rat and perhaps in several other species as well. Moreover, much of the species differences in the hyperglycemic activity of catecholamines can be attributed to their ability to stimulate hepatic glucose production on the one hand and to stimulate or inhibit insulin release on the other.


Cyproheptadine-induced depletion of insulin in the rat. The pancreotoxicity of cyproheptadine (CPH) in rats was characterized through measurement of proinsulin and insulin levels in the pancreas as well as plasma immunoreactive insulin (IRI) and glucose levels at various times during and after drug treatment. Daily oral doses of CPH (45 mg/kg) depleted pancreatic IRI to 25% of control within 3 days. Pancreatic IRI levels showed no further decrease during the rest of a 2-week treatment period and returned to normal levels 2 days after withdrawal of the drug. Pancreatic proinsulin levels were not significantly changed by CPH treatment, and the decrease in pancreatic IRI can be ascribed primarily to a decrease in insulin. Nonfasting hyperglycemia was evident after two doses of CPH and persisted throughout the treatment period. Plasma IRI was not significantly altered compared to control and was inappropriately low for the hyperglycemia that was produced by CPH. Daily doses of CPH given i.p. (45 mg/kg) caused a transient decrease in pancreatic IRI, but hyperglycemia did not occur. Lower i.p. doses (22.5 mg/kg/day) caused a sustained decrease in pancreatic IRI content to 45% of control after 2 weeks and hyperglycemia was evident throughout the treatment period. No changes in pasma IRI were observed as a result of drug treatment even though blood glucose was elevated. These results suggest that biochemical changes affecting insulin synthesis and/or storage are associated with previously reported CPH-induced morphologic alterations in the rat beta-cell.


Role of neonatal androgen in the development of hepatic microsomal drug-metabolizing enzymes. The development of several hepatic microsomal drug-metabolizing enzyme activities in rats was studied in relation to its androgen dependence during the neonatal period. Rats with their androgen deprived during the neonatal period (female rats and male rats castrated at birth) respond less to androgen treatment at adulthood for the metabolism of aminopyrine, ethylmorphine and hexobarbital as compared to rats exposed to neonatal androgen (male rats, male rats castrated at birth but neonatally treated with androgen and male rats castrated at the age of 20 days). This difference in the degree of hepatic responsiveness, however, varied with the substrates: ethylmorphine N-demethylase activity was affected the most whereas aminopyrine N-demethylase and hexobarbital oxidase activities were only marginally affected. Furthermore, these differences in responsiveness seem to be a delayed event, since hepatic aminopyrine N-demethylase activity in rats castrated at birth did respond to androgen stimulation during the prepubertal period and became insensitive to this same androgen stimulation at adulthood. The effect of neonatal androgen on the apparent Michaelis constant (Km) of ethylmorphine N-demethylase was also studied in the adult rat. Rats castrated at birth had a Km value (0.75 plus or minus 0.15 mM) similar to that of the females (0.95 plus or minus 0.13 mM). However, rats castrated at birth but neonatally treated with androgen and rats castrated at the age of 20 days exhibited Km values (0.29 plus or minus 0.06 and 0.25 plus or minus 0.06 mM, respectively) similar to that of the males (0.35 plus or minus 0.15 mM). The significance of neonatal androgen in the development of hepatic microsomal drug metabolizing enzyme system is discussed.


The effect of acetazolamide and carbonic anhydrase inhibition on erythrocyte 2,3-diphosphoglycerate content and metabolism. Experiments were designed to test the hypothesis that the change in erythrocyte 2,3-diphosphoglycerate (2,3-DPG) content which occurs when metabolic acidosis is induced by prolonged inhibition of carbonic anhydrase in vivo is the same as that which occurs with the induction of other types of metabolic acidosis states. 1) Thirteen-hour infusions of nondiuretic doses of a potent carbonic anhydrase inhibitor, acetazolamide (Diamox) did not alter erythrocyte 2,3-DPG levels in rats. 2) In vitro incubation of whole blood from rats for 10 days with high concentrations of two carbonic anhydrase inhibitors failed to alter the red cell content of 2,3-DPG. 3) Purified human carbonic anhydrase B had no phosphatase activity on 2,3-DPG and it appears unlikely that the enzyme hydrolyzes other phosphate esters of the erythrocyte which could indirectly alter 2,3-DPG content. 4) Acetazolamide administered in diuretic doses for 8 days to rats induced a metabolic acidosis which was accompanied by a decrease in erythrocyte 2,3-DPG. The change in 2,3-DPG content was similar to that produced by other methods of producing metabolic acidosis, namely NH4Cl treatment and nephrectomy. It appears that changes in 2,3-DPG content associated with effects of carbonic anhydrase inhibition can be ascribed to the metabolic acidosis resulting from the action of these drugs on the kidney.


Correlation of brain levels of barbiturate enantiomers with reported differences in duration of sleep. The concentrations of R(+)-and S(-)-pentobarbital and R(+)-and S(-)-secobarbital were determined in the brain stem, hypothalamus, cerebellum and cortex of mice after i.v. administration. No regional differences in enantiomer concentration or barbiturate/metabolite ratio were observed to account for the substantial potency differences reported for the enantiomeric forms of pentobarbital and secobarbital. Stereoselective differences in the rate of enantiomer metabolism and in stereochemical fit to the central nervous system receptor are discussed as possible reasons for the differences in duration of action.


Actions of the antidepressant drug imipramine on the voltage-clamped Myxicola giant axon. The effects of the antidepressant drug imipramine were studied on the voltage-clamped Myxicola giant axon at concentrations from 10- minus 6 to 5 X 10- minus 5 M. Over this range, imipramine reversibly reduced both the sodium and potassium conductances without having any substantial effect on either the resting membrane potential or the leakage conductance. The observed dose-response relation is described by a Langmuir adsorption isotherm with an apparent dissociation constant of 9 X 10-minus 6 M. The sodium and potassium conductance-voltage curves are shifted in the hyperpolarizing direction along the voltage axis, the magnitude of the displacement increasing with increasing concentrations of imipramine. There was no significant effect of imipramine on either time to peak sodium current or time to half-maximum steady-state current.


A choice procedure for drug reinforcers: cocaine and methylphenidate in the rhesus monkey. A choice procedure was developed to compare the reinforcing efficacy of drug solutions delivered via intravenous catheters to rhesus monkeys. Choices were arranged between doses of cocaine or methylphenidate and saline, different doses of the same drug and doses of both drugs. In each session, monkeys were allowed to self-inject one solution five times in the presence of a stimulus. Thirty minutes after the fifth injection, a second solution could be self-injected five times in the presence of a different stimulus. Thirty minutes later, choice trials began in which both stimuli were present and monkeys could choose one of the two solutions. Rate of responding decreased with increases in dose for both cocaine (0.05-1.5 mg/kg) and methylphenidate (0.075-0.7 mg/kg). Response rates maintained by cocaine were 2 to 3 times higher than those maintained by methylphenidate. Drug was always chosen over saline. Higher doses of cocaine were preferred to lower doses except when both were above 0.5 mg/kg, when no preference was shown. Higher doses of methylphenidate were preferred over low doses, but compared to cocaine, a greater absolute difference between dose magnitude was required to demonstrate preference. When equal doses of cocaine and methylphenidate were compared, no preference was shown. On other comparisons between the drugs, the higher dose was generally preferred regardless of the drug. The reinforcing efficacy of drugs must be considered not only in terms of response rate maintained or reinforcement schedule but also with reference to concurrently available drugs.


Interresponse time changes as a function of water deprivation and amphetamine. Drug effects on operant behavior are often characterized by their effects on rate of responding, usually expressed as the number of responses per unit of time. The time between two consecutive responses constitutes an interresponse time (IRT), and this measure has been used also to characterize the effects of drugs on operant behavior. IRTs which occur during a session can be classified on a statistical basis as: 1) short-IRT, an IRT(s) of short duratio generated by high-frequency responses; 2) pause, an IRT of long duratio generated by low-frequency responses; and 3) post-reinforcement pause, an IRT which immediately follows reinforcement. This investigation used three schedules of water reinforcement (fixed-ratio 20, fixed-interval 90-seconds and variable-interval 20-seconds) to examine how these IRT classes are influenced by changes in water deprivation conditions or amphetamine administration. Base-line IRT distributions depended upon the schedule of reinforcement. Changes induced by doses of amphetamine or alterations in level of water deprivation were compared and contrasted. Short-IRTs that characterized fixed-ratio 20 performance were resistant to change with increasing doses of amphetamine, but were increased in duration with decreasing water deprivation. Animals responding on a fixed-interval 90-second schedule showed a decreased postreinforcement pause after amphetamine, but an increased postreinforcement pause after access to water. An additional experiment studied the combined effects of presession water consumption and d-amphetamine administration on variable interval performances. Making water available before the session lowered the amphetamine dose-response curve along the vertical axis, suggesting that amphetamine did not mimic satiation. In most cases the effect of amphetamine and changing levels of water deprivation were dissimilar in their effects on IRT distributions, suggesting that amphetamine does not exert its major action on behavior through its adipsic effect.


Excitation and contraction in bovine tracheal smooth muscle. 1. The smooth muscle layer of the bovine trachea was studied in vitro with the micro-electrode and sucrose-gap techniques. The membrane potential was stable at--47-6 plus or minus 0-98 (S.E. of mean) mV, and there was no spontaneous electrical or mechanical activity. 2. The cell membrane had strong rectifying properties, making it impossible to elicit action potentials by electrical stimulation in normal Krebs Solution. The rectification was abolished by TEA (30 mmol/l), which depolarized the membrane and produced plateau-type action potentials. 3. The spontaneous repetitive action potentials produced by TEA were associated with rhythmic oscillatory contractions of the muscle strips. 4. Histamine caused an increased tone, with superimposed rhythmic fluctuations in tension. The electrical response consisted of depolarization, with rhythmic slow oscillations in potential (slow waves) which were synchronous with the fluctuations in tension. 5. Acetylcholine produced smooth, tonic contractures of tracheal muscle strips, and caused simple depolarization of the membrane. No action potentials were recorded. 6. In calcium-free solutions containing EGTA, the mechanical response to TEA was completely abolished; the response to histamine was greatly reduced; the response to acetylcholine was reduced to a lesser extent. All responses reverted to normal when normal concentrations of extracellular calcium were restored. 7. Lanthanum added to the bathing solution abolished the contraction due to TEA even though the solution contained calcium. It reduced the histamine-induced contraction to 26% of control, and reduced the acetylcholine-induced contraction to 58% of control; extracellular calcium was present throughout. 8. It is suggested that TEA produces contraction by promoting influx of calcium ions into the cytoplasm. Acetylcholine, and to a smaller extent histamine, are less dependent upon the presence of extracellular calcium, and may be capable of releasing calcium sequestered within the cell; acetylcholine appears to be more effective in releasing sequestered calcium.


Natural convection around the human head. 1. Factors determining the convective flow patterns around the human head in 'still' conditions are discussed in relation to body posture. 2. The flow patterns have been visualized using a schlieren optical system which reveals that the head has a thicker 'insulating' layer of convecting air in the erect posture than in the supine position. 3. Local convective and radiative heat transfer measurements from the head have been using surface calorimeters. These results are seen to be closely related to the thickness of the convective boundary layer flows. 4. The total convective and radiative heat loss from the head of a subject in the erect and supine position has been evaluated from the local measurements. For the head of the supine subject the heat loss was found to be 30% more than when the subject was standing.


Forced convection around the human head. 1. The parameters determining the forced convective heat loss from a heated body in an air stream are outlined. 2. Local forced convective heat transfer distributions around the human head and a heated vertical cylinder at various wind speeds in a climatic chamber have been found to be similar and related to the aerodynamic flow patterns. 3. From the local convective coefficient distribution, values for the overall convective coefficient h-c at various wind speeds have been evaluated. These are seen to agree closely with existing whole body coefficients determined by other methods.


The relationship between elevated water intake and oedema associated with congestive cardiac failure in the dog. 1. In the dog constriction of the thoracic region of the inferior vena cava increases water intake and extracellular and plasma fluid volumes. 2. Restriction of water intake to the pre-operative level for 2 weeks reduces the measured extracellular fluid volume to the pre-operative level. 3. Administration of the competitive angiotensin inhibitor, saralasin acetate, to two dogs in congestive cardiac failure following thoracic caval constriction markedly reduced their water intake. 4. These results suggest that increased fluid intake is probably important in the aetiology of the oedema associated with congestive cardiac failure, probably through the renin-angiotensin system.


Studies on the mechanism of fibrillation potentials in denervated muscle. 1. Intracellular electrodes were used to study the origin of fibrillation potentials in chronically denervated rat muscle. 2. Fibrillation potentials were observed to start from spontaneous biphasic membrane potential oscillations. Each action potential was followed by an after-hyperpolarization which in turn served as a pre-potential for the next spike. The critical level (threshold) for the initiation of the first spike in a train was lower than that of the next and subsequent spikes. 3. A correlation was found between the level of membrane potential and the critical level for action potential generation. This relation was most marked around the resting membrane potential (minus 60 to minus 80 mV) where 10 mV hyperpolarization caused a 9 m V increase in the critical potential level. At higher membrane potentials the correlation was less pronounced. In innervated muscles a similar correlation existed but it was less marked and was present only at membrane polarizations below the resting potential. 4. Increasing the external calcium concentration from 2 to 8 mM reduced the membrane potential-critical level relationship in denervated fibres towards that of innervated ones. 5. As critical level changes with membrane hyperpolarization, the rate of rise of the action potential increased, suggesting a progressive removal of sodium inactivation. 6. It is suggested that a mechanism similar to anode break excitation is important for the induction and maintenance of fibrillation potentials.


Drinking behaviour in the cat induced by renin, angiotensin I, II and isoprenaline. 1. Angiotensin I, II and hog renin, infused into the lateral cerebral ventricles (I.C.V.) of water replete cats, each induced water drinking behaviour. 2. Intravenous infusion of high doses of angiotensin I or II also elicited a drinking response. The dipsogenic effect of I.V. renin was not marked. 3. Drinking in response to I.C.V. angiotensin II was abolished after autonomic ganglion blockade with I.V. hexamethonium or pempidine and was significantly reduced after I.V. atropine methonitrate. 4. The dipsogenic response to I.C.V. angiotensin II was unaffected by either peripheral adrenergic neurone blockade with I.V. bethanidine, alpha-adrenoceptor blockade with phentolamine or beta-adrenoceptor blockade with sotalol. 5. Atropine, atropine methonitrate, hexamethonium and pempidine given I.C.V did not inhibit the diposgenic response to I.C.V. angiotensin II. 6. Bethanidine I.C.V. produced a dose related reduction in the dipsogenic response to I.C.V. angiotensin II. 7. The alpha-adrenoceptor blocking agents tolazoline and phenoxybenzamine given I.C.V did not affect angiotensin induced drinking but the response was regularly inhibited by phentolamine I.C.V. 8. The beta-adrenoceptor blocking agents propranolol and practolol given I.C.V. each inhibited angiotensin induced drinking. The L-isomer of propranolol was a more effective blocker than the D-isomer. 9. Isoprenaline given I.C.V induced drinking in ten of sixteen cats. Subcutaneous administration of isoprenaline also elicited drinking but the onset of the response was delayed and the amount consumed slightly less than after I.C.V infusion.


Electrical activity of grafted myometrium and its recording by radio-telemetry in unrestrained rabbits. 1. The electrical activity in myometrial grafts in fifty-one female rabbits with ear chambers fitted with pick-up electrodes has been monitored. An FM telemetry system has made long-term studies possible in the freely moving animal. 2. Two distinct patterns of electrical activity were observed either arising spontaneously or provoked by oxytocin. These were the 'long-duration burst' containing about 50-150 spikes, and the 'short-duration burst' containing 1-10 spikes. 3. The spike frequency within the long-duration bursts varied between 0-9 and 1-3 spikes sec-1 and was fairly constant during the first half of the burst. The frequency of the bursts in the long series of short-duration bursts was about 2-3 min-1. 4. When activity from grafts in two chambers in the same animal was monitored for long periods, spontaneous activity occurred at random throughout the day in each graft, indicating that the spontaneous activity was probably myogenic.


Pancreatic acinar cells: ionic dependence of acetylcholine-induced membrane potential and resistance change. 1. Intracellular recordings of membrane potential, input resistance and time constant have been made in vitro from the exocrine acinar cells of the mouse pancreas using glass micro-electrodes. The acinar cells were stimulated by acetylcholine (ACh). In some cases ACh was simply directly added to the tissue superfusion bath, in other experiments ACh was applied locally to pancreatic acini by micro-iontophoresis. 2. Current-voltage relations were investigated by injecting rectangular de- or hyperpolarizing current pulses through the recording micro-electrode. Within a relatively wide range (-20 to -70 mV) there was a linear relation between injected current and change in membrane potential. The slope of such linear curves corresponded to an input resistance of about 3-8 M omega. The membrane time constant was about 5-10 msec. 3. ACh depolarized the cell membrane and caused a marked reduction of input resistance and time constant. The minimum latency of the ACh-induced depolarization (microiontophoretic application) was 100-300 msec. Maximal depolarization was about 20 mV. The effect of this local ACh application was abolished by atropine (1-4 x 10-6 M). The blocking effect of atropine was fully reversible. 4. Stimulating with ACh during the passage of large depolarizing current pulses made it possible simultaneously to observe the effect of ACh at two different levels of resting potential (RP). At the spontaneous RP of about minus 40 mV ACh evoked a depolarization of usual magnitude (15-20 mV) while at the artificially displaced level of about -10 mV a small hyperpolarization (about 5 mV) was observed. It therefore appears that the reversal potential of the transmitter equilibrium potential is about -20 mV. 5. Replacement of the superfusion fluid C1 by sulphate or methylsulphate caused an initial short-lasting depolarization, thereafter the normal resting potential was reassumed...


A central osmosensitive receptor for renal sodium excretion. 1. The effect on renal Na and water excretion of increasing the NaCl concentration of blood supplying the brain was investigated in conscious water-loaded sheep. Intracarotid infusion ot 4 M-NACl at 0-8 ml./min for 60 min was compared with equivalent intrajugular infusion. 2. A more rapid increase in renal Na excretion and urine osmolality occurred with the intracarotid infusions than with intrajugular infusions. 3. Intracarotid infusions of 2 M sucrose or fructose at 1-6 ml./min for greater increase in renal Na excretion, urine osmolality and a decrease in urine flow rate. 4. The results suggest that there are receptors in the brain sensitive to changes in extracellular tonicity which influence renal Na excretion. It is possible that changes in ADH secretion alone mediate the early natriuresis seen with intracarotid hypertonic infusions although an alternative concurrent mechanism cannot be ruled out.


Circadian rhythms in the flow rate and composition of unstimulated and stimulated human submandibular saliva. 1. Nine subjects recorded oral temperature and collected unstimulated submandibular saliva and submandibular saliva stimulated by sour lemon drops at a constant flow rate of 1 ml./min, at about 07.00, 11.00, 14.00, 17.00 and 22.00 h daily for time spans of about 11 days. 2. Least-squares cosine waves were fitted to the data to test for the presence and characteristics of circadian rhythms and the results were subjected to cosinor analysis and the Rayleigh test to assess the statistical significance of any rhythms for the group of subjects as a whole (i.e. whether or not the computed acrophases were randomly distributed throughout the 24 h of the day). 3. Unstimulated submandibular saliva showed circadian rhythms, significant for the group as a whole, in flow rate and in the concentrations of sodium, potassium, magnesium, chloride and inorganic phosphate but not in protein or calcium. 4. Stimulated submandibular saliva showed circadian rhythms, significant for the group as a whole, in sodium, potassium, calcium, magnesium, chloride and inorganic phosphate but not in protein. Oral temperature also showed a significant circadian rhythm. 5. Because of the high amplitude of many of these rhythms, they must be taken into account when establishing the normal range of salivary values, or when salivary composition is to be used as an indicator of systemic disease or to be implicated in the aetiology of oral disease.


Effects of noradrenaline infused into the chick hypothalamus on thermoregulation below thermoneutrality. 1. Hypothermia induced by infusion of noradrenaline into the hypothalamus of 2-3 week old chicks, within their thermoneutral range, was considerably potentiated by lowering ambient temperature. 2. Noradrenaline-induced hypothermia was associated with reduced carbon dioxide elimination and reduced blood lactate concentrations whereas leg temperature, electromyographic activity, plasma NEFA and plasma glucose concentrations were increased. 3. Mechanisms postulated to explain the phenomenon are inhibitory and facilitatory effects of noradrenaline on some, but not all, heat production and heat loss mechanisms. Increased electromyographic activity after intrahypothalamic noradrenaline is assumed to be due to lack of effect of noradrenaline on spinal thermosensitive centres; increased plasma NEFA concentration may be due to inhibition of NEFA utilization.


Variability of the relative preference for stimulus orientation and direction of movement in some units of the cat visual cortex (areas 17 and 18). 1. The responses to visual stimuli of single units in the cortex of cats anaesthetized with pentobarbitone were recorded extracellularly with glass micropipettes. All had receptive field centres more than 5 degrees and most lay between 5 and 20 degrees from the area centralis. Most units were in Area 18 but some were in the corresponding field representation in Area 17. 2. A quantitative method is described in which the visual stimuli (slits or light bars) were presented repetitively by mechanical means in each of four orientations of the stimulus and in two directions of movement for each orientation. The responses were analysed quantitatively and criteria are described for classification of units according to their preference for particular orientations or directions of movement of the stimulus. 3. Some units were studied continuously for up to 2 hr using the quantitative technique. In Area 18, of nineteen units, eighteen showed changes in their preference for direction of stimulus movement and, in seven of eleven units, the orientation preference changed. In Area 17 direction preference changed in eight of nine units and orientation preference in six of seven. In some cases both orientation and direction preference altered. 4. The relationship of these changes to alterations in the 'spontaneous activity' of the cortical units and to variations in the depth of anaesthesia are considered. Neither would appear to be the sole cause of the phenomenon.


The effect of a chronic lesion in cortical area 17 on the visual responses of units in area 18 of the cat. 1. Lesions were made in cortical Area 17 (Visual I) of eight cats which were then allowed to recover. 2. During acute experiments between 1 and 11 weeks after the lesion the activity of Area 18 (Visual II) units was recorded and the results were compared with those obtained in normal cats. 3. The receptive fields were similar in size and distribution in the two groups but the lesioned animals had a much higher proportion of units unaffected by a visual stimulus and a higher proportion of the visually responsive units lacked specific direction or orientation preference. 4. Of six units which were tested in Area 18 of cats with lesions five showed variability of their direction or orientation preference with time. 5. The effects described above are most probably due to destruction of the corticocortical pathway which connects Areas 17 and 18. Some units in Area 18 appear to be driven by visual stimuli via their geniculate input alone. The corticocortical (Area 17 to 18) pathway may normally confer additional specificity on some of these units.


Muscle tension during unrestrained human eye movements. 1. Tensions in the horizontal rectus muscles have simultaneously and continuously been recorded during unrestricted eye movements in four strabismus patients, using force transducers small enough to be implanted in series between the tendons and their points of insertion on the globe. 2. Levels of tension required to maintain fixation at each position of gaze vary from a minimum of 8-12 g approximately 15 degrees outside of muscle's field of action to a maximum of around 40 g at extreme gaze within the muscle's field of action. When tension is plotted as a function of eye position, the static locus of fixation tension levels exhibits a parabolic relationship. 3. Tensions recorded during smooth following movements parallel or slightly exceed those of fixation. 4. At the onset of a saccade, tension in the agonist rises isometrically, then, as the eye moves, tension levels parallel those of fixation but with an isotonic increment of 15-25 g. At the end of the saccadic movement, tension falls essentially isometrically to the new fixation level. 5. Tension in the antagonist reveals an unexpected peak at the onset of a saccade. 6. For saccadic movements tension increments of 15-25 g above the fixation levels suffice to move the eye rapidly to a new position of gaze, regardless of the duration of the saccade and the location of the new fixation point. 7. Maximum and minimum levels of tension during normal fixation, following and saccadic movements, plotted as a function of eye position, form an operational envelope which defines the limits of muscle forces during normal eye movements. The lowest level of this envelope is the parabolic static locus of fixation tensions.


An electrophysiological and morphological study of normal and denervated chicken latissimus dorsi muscles. 1. Some electrophysiological and morphological properties of 'fast' (singly innervated) and 'slow' (multiply innervated) muscle fibres were studied in normal and denervated posterior and anterior latissimus dorsi muscles of the young chickens. 2. Normal singly and multiply innervated muscle fibres are capable of generating action potentials which in all qualitative respects are similar. 3. The action potentials of multiply innervated muscle fibres are of lower amplitude and slower maximum rate of rise than action potentials in singly innervated muscle fibres. 4. Denervation causes the resting membrane potential and the maximum rate of rise of the action potential to fall. The changes are greater in singly innervated than in multiply innervated fibres, but in neither case are as great as in mammalian skeletal muscle fibres after surgical denervation. 5. In neither singly nor multiply innervated muscle fibres do the action potentials generate any 'resistance' to tetrodotoxin as a result of denervation. 6. The diameter of multiply innervated fibres is increased after denervation, but it is reduced in singly innervated fibres. The number of myofilaments increases in multiply innervated fibres, but decreases in single innervated fibres. In both types of muscle fibre the volume fraction of myofibrils is decreased. 7. In the singly innervated muscle fibres there is an increase in the volume fraction of mitochondria. 8. In the singly innervated muscle fibres, there is some rearrangement of the membrane systems in that some of the transversely orientated triads are replaced by longitudinally orientated dyads.


Duodenal control of gastric emptying in the milk-fed calf. 1. It has been ascertained experimentally that an open duodenal cannula does not cause any marked variation in emptying of the abomasum when compared to the rate of emptying of the normal viscus or when the cannulae are closed. 2. Duodenal re-entrant cannulae provide a preparation whereby it is possible to infuse the duodenum via the distal cannula and to collect simultaneously the effluent fluid of the abomasum from the proximal arm of the cannula (Fig. 1). 3. With this preparation the duodenal infusate is not contaminated by the gastric effluent and thus the duodenal stimulus can be restricted to the single non-varying effect of the infusate. 4. In the milk-fed calf using this preparation the following facts have been established. (a) On infusion into the duodenum, hypotonic and isotonic solutions of sodium chloride and sodium bicarbonate increase abomasal emptying; bicarbonate being the more effective stimulus. (b) Potassium chloride, calcium chloride, glucose and hydrochloric acid inhibit gastric emptying when infused into the duodenum. (c) Ammonium chloride, urea, lactose and acetic acid have little effect. (d) Hypertonic solutions of all substances tested were inhibitory to gastric emptying when infused into the duodenum. 5. It has been demonstrated unequivocally that it is the effect of the infusate in the duodenum which controls gastric emptying for when the stomach is isolated from the duodenum, gastric emptying can be manipulated from the duodenum whatever the stomach contents may be. 6. Our results bring firm experimental confirmation of the views discussed by Hunt & Knox (1968) that gastric outflow is regulated by mechanisms initiated from receptors situated in the duodenum.


Organization of climbing fibre projections to the cerebellar cortex from trigeminal cutaneous afferents and from the SI face area of the cerebral cortex in the cat. 1. In cats anaesthetized with pentobarbitone, the projection of climbing fibres (CFs) to the cerebellar cortex from trigeminal cutaneous branches and from the face area of the sensorimotor (SI) cortex was mapped, using the technique of laminar field potential analysis. 2. The CF projections from both the trigeminal nerve and the SI face area were found to be localized to the same cerebellar folia, viz. chiefly the ipsilateral lobule HVI, with a small overlap on to the adjacent folia of lobule V and crus Ia of HVIIA. Frequently a projection from the superficial radial nerve to part or all of this area, was also found. 3. A correspondence in the distribution and amplitudes of CF potentials evoked at most points by stimulation of the trigeminal nerve and the SI cortex was found. This implies a convergence of afferents from these two sources at or before the inferior olive. 4. In more than half of the cats, a small area of the cerebellar hemisphere was found, in which contralateral as well as ipsilateral trigeminal stimulation would evoke CF potentials. Usually inputs from the superficial radial nerve and the SI cortex also converged upon this area. 5. The organization of CF projections from trigeminal and superficial radial nerve afferents to the cerebellar hemisphere was found to occur in the same 'patchy' pattern of somatotopy that has been described for spinal nerve inputs to the anterior lobe. 6. One constant factor was found in the pattern of organization of CF projections to this area from cutaneous afferent nerves. That is, only the afferents from overlapping areas of skin projected to a given recording point: no instance of CF projections from trigeminal branches innervating discontinuous skin areas was observed.


Climbing fibre inputs to cerebellar Purkinje cells from trigeminal cutaneous afferents and the SI face area of the cerebral cortex in the cat. 1. An investigation was made of climbing fibre (CF) activity evoked in single Purkinje cells in the cerebellum by electrical stimulation of trigeminal cutaneous afferents, the face area of the SI cortex, and the superficial radial nerve, in Nembutal-anaesthetized cats. In addition, both the extent of the cutaneous receptive fields of individual Purkinje cells on the face and the CF responses evoked in these cells by controlled natural stimulation were examined. 2. The pattern of convergence from these inputs on to individual Purkinje cells was found to be complex. DF responses were evoked in 67% of trigeminally-activated cells by electrical stimulation of more than one trigeminal branch. An excitatory CF convergence from the face area of the SI cortex was found on 68% of trigeminally activated cells; 23% also responded to stimulation of the superficial radial nerve. 3. In 81% of the Purkinje cells which were activated by trigeminal nerve stimulation, CF responses were readily elicited by gentle mechanical stimulation of the facial skin. A qualitative relationship was established between the size of the peripheral field of a Purkinje cell, and the probability of convergence on to that cell from the SI cortex. 4. Recordings were made from a limited number of Purkinje cells which were responsive to electrical stimulation of bilateral trigeminal branches and the superficial radial nerve. However, CF responses in these cells often could be elicited only by high intensity stimulation. It is suggested that these cells are analogous to, or perhaps an extension of the population of Purkinje cells described in the anterior lobe which are excited via the ventral funiculus pathway in the spinal cord only by stimulation of 'flexor reflex afferents' in bilateral limb nerves.


An analysis of the release of acetylcholine from preganglionic nerve terminals. 1. A study has been made of the release of acetylcholine (ACh) from the preganglionic nerve terminals of the isolated superior cervical ganglion of the guinea-pig during short trains of impulses, using the amplitude of the excitatory post-synaptic potential (e.p.s.p.) as a measure of the ACh released by each impulse. 2. The time course of decay of facilitation following a single impulse could be described by two exponential components, with T1 = 200 msec, and T2 = 13-3 sec. The increase in ACh output at the beginning of stimulation at frequencies smaller than or equal to 2Hz was reasonably predicted in terms of summation of the individual facilitatory effects of each impulse in the train, but fell short of the prediction at higher frequencies. 3. The steady-state output of ACh during repetitive stimulation at frequencies between 0-5 and 20 Hz was lower than that predicted by summation of the facilitatory effects of each impulse, but reached the predicted level at frequencies smaller than or equal to 2Hz in raised Mg2+ concentrations. 4. Statistical analysis of the quantal content (m) of e.p.s.p.s evoked by each of the first five impulses in a train showed that Poisson statistics described release of ACh at the beginning of a train in most cases; when binomial statistics could be applied (two of seven axons studied), the increase in m was accompanied by an increase in the statistical parameter, n. 5. Analyses were also made of release during continuous stimulation; at the time when the steady state of release was reached, the statistical parameter, p, had also increased. Increased release of ACh at increased frequencies of stimulation was associated with increases in p in axons with p smaller than 0-5; however, in most axons (eleven of seventeen), p was greater than 0-5 in the steady state, and increases in m with frequency were due to increases in n.


Biosynthesis of histamine and putrescine in mice during post-natal development and its hormone dependence. 1. Histidine decarboxylase and ornithine decarboxylase activities were determined in mouse kidney and liver during post-natal development. 2. The content of histamine, putrescine, spermidine and spermine was examined in kidney and liver and in the urine of adult male and female mice. 3. Histamine formation by the kidney was high in both sexes when determined a few days after birth but decreased during weaning. Thereafter, a distinct sex difference was established in that in the female kidney the level of histidine decarboxylase rose several-fold during adolescence while in the male the level was still further reduced. 4. Putrescine formation by mouse kidney was low in both sexes up to three weeks of age whereafter the amine formation in the male increased conspicuously whereas that of the female kidney remained low. 5. The observed sex differences in tissue enzyme activities were reflected in concomitant differences in the amount of the diamines excreted in the urine. 6. No correlation was found between the actual enzyme levels and the assayed tissue content of histamine, putrescine, spermidine and spermine. 7. Following gonadectomy, the activities of both decarboxylases were significantly altered. Ornithine decarboxylase activity of male kidney and histidine decarboxylase activity of female kidney were strikingly reduced. 8. In the mouse liver, the two decarboxylases displayed no changes comparable with that of the kidney during development.


Interrelationships of the volume and time components of individual breaths in resting man. 1. The volume and time components of individual breaths have been investigated under 'steady-state' conditions during air-breathing in fifteen subjects and, in a further six subjects, also during the addition of 1-5 and 3% CO2 to the inspired gas. 2. A computer-assisted method has been used to derive from the air flow record the individual breath values of tidal volume (VT), inspiratory duration (TI), expiratory duration (TE) and cycle duration (TC = TI + TE) for a sequence of breaths in the various steady-state conditions. 3. When the subjects were breathing room air, for breath sequences of over 200 breaths (n = 228-365), mean values of TI (TI) mostly lay between 1 and 2-5 sec, TE between 2-0 and 3-5 sec and VT between 0-4 and 0-91. The distributions of VT, TI and TE were in general unimodal. 4. Significant negative correlations between VT and F, and positive correlations between VT and TC, have been confirmed. 5. In all fifteen subjects, a highly significant positive correlation existed between VT and TI (mean r = +0-704), which was stronger than that between VT and TC (mean r = +0-533). Weaker positive correlations were demonstrated between VT and TE, and between TI and TE (mean r = +0-359 and +0-381 respectively). 6. The intercept of the regression of VT on TI passed close to the origin, typically slightly positive on the VT axis (mean = +0-0991.). This, coupled with the strong positive correlation between VT and TI, indicates that the mean inspiratory flow rate (VI = VT/TI) for each breath is held relatively constant from breath to breath. 7. In the six subjects studied during CO2 inhalation, the mean % contributions of VT and F to the increase in ventilation associated with breathing 3% CO2 were 75 and 25% respectively. 8. At the three different levels of ventilation, neither VT, TI nor TE showed a wholly consistent trend, although VT tended to increase, TE to decrease and TI to be unchanged. In contrast, the average values of VI (VI) consistently increased as the chemical stimulus was raised. 9. It is concluded that the previously observed tendency for ventilation to be held constant from breath to breath during steady-state breathing depends predominantly on the tendency for VI to be held constant. Close restraints are evidently not imposed on the individual values of VT and TI under these conditions. The neural mechanism generating breathing appears to control ventilation principally by regulating the rate of inspiratory air flow and secondarily TE.


Contribution of an electrogenic sodium pump to membrane potential in mammalian skeletal muscle fibres. 1. Relationship between the resting membrane potential and the changes in the intraceullar Na and K concentrations ([Na]i and [K]i) was studied in 'Na-loaded' and K-depleted' soleus (SOL) muscles of rats which had fed a K-free diet for 40 and more days. 2. The extracellular space of the muscles was not significantly different between normal and K-deficient rats. The inulin space in both the 'fresh' and Na-rich' muscles can be determined by the same function relating the space to the muscle weight. 3. Presence of 2-5-15 mM-K in the recovery solution hyperpolarized the 'Na-rich' muscul fibres at the beginning of recovery. The hyperpolarized membrane potential exceeded, beyond the measured potential  of 'fresh' muscle fibres, the theoretical potential derived from the ionic theory, or even beyond Ek. Then, the measured membrane potential declined progressively during the immersion in a recovery solution and returned to the steady-state value When a considerable Na extrusion and K uptake took place, the measured membrane potential became equal to Ek. 4.he maximal hyperpolarization occurring immediately after immersion in the recovery solution became smaller and had a shorter duration when increasing the external K concentration ([K]o) from 2-5 to 15mM. 5. The K-sensitive hyperpolarization was completely abolished on exposure to 0mM [K]o, on cooling to ca. 4 degrees C, and in the presence of oubain (10(-4) M). The inhibitory effects were reversed on returning to the control conditions. The membrane potential obtained after inhibition of the electrogenic Na-pump with cooling or ouabain agrees well with that predicted by the 'constant-field' equation. 7. The external Cl ions had a short-circuiting effect on the electrogenic Na-pumping activated on adding K ions. 8. The replacement of Na ions in a recovery solution with Li ions resulted in a faster rate of depolarization from the maximal hyperpolarizationp. It is concluded that the resting membrane potential of 'Na-loaded' and 'K-depleted' SOL muscle fibres is the sum of an ionic diffusion potential predicted by either the Nernst equation or the constant-field equation and of the potential produced by an electrogenic Na-pump.


The effect of sodium salicylate on bile secretion in the dog. 1. The I.V. injection of sodium salicylate (100 mg/kg) in the dog caused a rapid and maintained choleresis of the order of 300-600 percent of control levels. 2. The total amount of salicylate excreted in bile was only 1-2 percent of that injected. 3. The secretion of bile salt into bile was not increased by salicylate. 4. The choleresis caused by salicylate was associated iwth a decrease in the concentrations of sodium and of bile salt in bile, and with an increase in the concentration of chloride; the biliary concentration of bicarbonate was either temporarily increased or unchanged. 5. The choleresis could not be inhibited by the intra-portal injection of of ouabain (0-1 mg/kg). 6. The secretion of bromsulphthalein into bile was not potentiated by the choleresis. 7. The choleretic efficiency of sodium taurocholate was not increased in the presence of salicylate. 8. The injection of acetazolamide (20 mg/kg) in the presence of a salicylate choleresis, caused an increase in the osmolaity of bile and an increase in biliary sodium concentration, such that the composition of bile more nearly approached that of plasma. 9. The possible mechanisms underlying the choleretic effect of sodium salicylate are discussed.


Aspects of bile secretion in the rabbit. 1. Bile secretion was studied in anaesthetized rabbits from whom hepatic bile was collected by cannulation of the common bile duct. 2. The flow and composition of bile formed by rabbits anaesthetized with urethane differed significantly from that formed by rabbits anaesthetized with pentobarbitone sodium. 3. The I.P. injection of a hypertonic solution of sucrose (3 M) decreased bile flow and produced changes in the ionic composition of bile and of plasma. 4. The infusion of sodium taurodeoxycholate (1-5-20 mumole/min I.V.) gave higher rates of bile flow than did equimolar infusions of sodium taurocholate, and unlike taurocholate, increased the bicarbonate concentration of bile. 5. Acetazolamide (10-100 mg/kg) increased the concentration of bicarbonate both in bile and in plasma, and had little effect on bile flow. 6. The infusion of bromsulphthalein (5 mg/kg I.V.) decreased the excretion of bicarbonate into bile, and was associated with the formation of a hypotonic bile. 7. The implications of these results in relation to the mechanisms of bile secretion are discussed.


Comparative effects of sodium taurodeoxycholate and sodium taurocholate on bile secretion in the rat, dog and rabbit. 1. The biliary effects of sodium taurodeoxycholate and sodium taurochloate were investigated in anaesthetized dogs and rats, and in the isolated perfused rat liver. 2. Both bile salts had similar qualitative and quantitative effects on the flow and composition of bile in the dog. 3. In the rat, the bile salts had similar effects on the ionic compoistion of bile, but differed in that bile flow was not always directly related to the rate of bile salt secretion in bile, in the experiments with sodium taurodeoxycholate. 4. Sodium taurodeoxycholate is hydroxylated form sodium taurocholate by the liver of the rat but not by that of the dog. 5.The biliary effects of sodium taurodexoycholate in the rat and in the dog are contrasted with its effects in the rabbit, and the differences between the three species are discussed.


The electrogenic sodium pump in the hyperpolarizing and secretory effects of pancreozymin in the pancreatic acinar cell. 1. Transmembrane potential, effective membrane resistance, and amylase release were recorded simultaneously from acinar cells of isolated rat pancreas perfused with Krebs-Henseleit solution. 2. The hyperpolarizing effect of pancreozymin (Pz) was confirmed by perfusing with a solution containing 5 m-u. Pz/ml. 3. The hyperpolarizing effect of Pz disappeared in the following environments: (a) in low ambient temperature, (b) in K-free medium, (c) in low Na medium, and (d) in the presence of ouabain. In these environments, transient depolarization was frequently observed immediately after stimulation. It is suggested that there are two components in the effect of Pz on the membrane potential of the acinar cells: transient depolarization which coincides with an increase in Na permeability in the initial phase, and continuous hyperpolarization due to an electrogenic Na pump which conceals transient depolarizing phase when the pump is dominant. 4. The secretory effect of Pz was inhibited under conditions that suppressed the electrogenic Na pump. It is proposed that the Na pump activated by Pz maintains the passive Na-influx, increases [Ca2+]i, and, in consequence, uphold the amylase output during continuous stimulation. 5. A medium which was used to bathe the sectioned pancreas with Pz was found to contain a substance which depolarized the acinar cells.


Responses of fastigial nucleus neurones to stimulation of the caudate nucleus in the cat. 1. Extracellular records were made of single unit activity evoked in the fastigial nucleus (FN) by electrical stimulation of the caudate nucleus (CN) in cats anaesthetized with sodium thiopentone. 2. Single shock stimulation evoked bilaterally complex responses having up to three components. These were, in temporal order, with percent of units exhibiting them, (a) a short burst of evoked spikes with either a latency of smaller than 5-5 msec and no associated field potential (6 percent) or a latency of 7-5-20 msec and associated with a prominent negative-going field potential (36 percent); (b) suppression of spontaneous discharges for a period of 20-150 msec (90 percent); (c) a resumption of spike discharges with a transient increase in frequency lasting for  25-500 msec (66 percent). 3. Changes in component (c) of the response patterns of some units were noted during repetitive stimulation The nature of the change depended on the laterality of the FN with respect to the stimulated CN. 4. Mechanisms which might account for the responses are discussed, but  it is emphasized that some of the results cannot yet be satisfactorily explained.


Secretion of calcium in pancreatic juice. 1. The orgin of the calcium secreted by the pancreas has been investigated in vivo in the guinea-pig by a study carried out in parallel (a) in the juice secreted in response to the injection of either secretin or caerulein and (b) in the pancreatic tissue and in cell fractions isolated thereform. 2. In agreement with previous findings we observed that the concentration of calcium is low in the secretin-stimulated and high in the caerulein-stimulated juice. In the latter calcium and protein are proportional (cal0 n-mole:mg). 3. After I.V. injection of 45Ca the radioactivity decreases rapidly and quasi-exponentially in the blood plasma. A roughly parallel time course is found in the secretin-stimulated juice: the evolution of the juice: plasma radioactivity ratio resembles that observed with the extraceullar space marker [3H]D-sorbitol. In contrast, the time course of 45Ca in plasma and caerulein-stimulated juice are not proportional: the high levels characteristic of this juice are reached several minutes after the injection and maintained thereafter. This increase is followed ca. 50 min later by the appearance of the newly synthesized [3H]L-leucine-labelled proteins. 4. The pancreatic tissue is rich in calcium which is localized primarily in zymogen granules (Ca.36 n-mole:mg protein) and mitochondria; the soluble cytoplasm is low in calcium. 5. The injected 45Ca accumulates in zymogen granules faster than [3H]L-leucine-labelled proteins. The 45Ca:protein ratio of these organelles is considerably lower than that of the caerulein-stimulated juice. 6. It is concluded (a) that calcium is secreted in to the pancreatic juice in two fractions, one (possibly released by simple diffusion) associated with the electrolyte component, the other with protein of the juice, (b) that zymogen granules are the major, but not the only source of the latter fraction, and (c) that the zymogen granule-associated calcium joins the exportable proteins some time after their synthesis, possibly in the Golgi complex and/or in the condensing vacuoles.


Periodic excitability changes across the receptive fields of complex cells in the striate and parastriate cortex of the cat. 1. Complex cells in cortical areas 17 and 18 of the cat have been studied in response to narrow slits and edges moving across the receptive field in the preferred direction and also to stationary slits of different widths. 2. Average response histograms, recorded as a narrow slit was moved across the receptive field, displayed a periodic series of peaks above a base line level. The response histogram for most area 17 and 18 cells contained five principal peaks; sometimes one or two weaker peaks were present at receptive field borders. The histogram for one cell located at the area 17-18 border showed thirteen distinct peaks. Periodic response patterns were also generated as an extended edge was moved across the receptive field. Plots of cell responses versus slit width for stationary slits of different widths also indicated periodic response pattern. 3. The accuracy of determining the preferred slit orientation was the single most important requirement for demonstrating the periodic response pattern. Significant changes in the appearance of the periodic pattern occurred even upon 5 degrees rotations away from the preferred orientation. 4. Average response histograms were also studied over a wide range of moving slit velocities. The number of peaks across corresponding spacings within the recewptive field remained constant over a range of velocities. Response amplitudes, however, were velocity dependent. Thus the response peaks remain associated with fixed positions within visual space independent of stimulus velocity, even though temporal as well as spatial factors may be involved in response selectivity and the periodic modulation. The most striking periodic response histograms were generated at the velocities which produced the greatest cell firing rates. Area 17 complex cells responded well to velocities of less than 0-5 degrees to 6-0 degrees/sec, but cells in area 18 generally required higher velocities, sometimes as high as 20 degrees--30 degrees/sec, for a good response. 5. Spatial frequencies for the periodic component of the receptive field for area 17 cells in the central visual area covered a range of three octaves up to 5 cycles/degree, and area 18 cells included another octave on the low frequency side. The spatial frequency of a cell was found to be roughly inversely proportional to the receptive field width. Only a small sample of area 18 cells was studied, but these cells tended to represent low spatial frequencies and to respond selectively to high velocity stimuli...


Baroreceptor and chemoreceptor influences on heart rate during the respiratory cycle in the dog. 1. Brief stimuli were delivered to the carotid chemoreceptors or baroreceptors in dogs anaesthetized with pentobarbitone or chloralose. Chemoreceptor stimulation was achieved by rapid retrograde injections of 0-2-0-5 ml. warmed, CO2-equilibrated saline through a cannula in the external carotid artery. Baroreceptor stimulation was achieved by forceful retrograde injection of 2-5 ml. air-equilibrated saline, or of freshly drawn arterial blood, into the external carotid artery after first clamping the common carotid artery. 2. Brief baroreceptor stimuli had no noticeable effect on breathing. Brief chemoreceptor stimuli had no effect on breathing in some dogs, but in many produced a reflex increase in the depth of inspiration when delivered during inspiration. In these same dogs, brief chemoreceptor stimuli delivered in expiration either prolonged the expiratory pause or evoked an active expiratory effort. 3. Prompt decreases in heart rate were elicited by brief sudden chemoreceptor or baroreceptor stimuli when these were delivered during the expiratory phase of respiration. The stimuli did not modify the control heart rate pattern when delivered during inspiration. If the carotid sinus nerve or the vagus nerves were cut the responses were abolished. 4. Brief chemoreceptor or baroreceptor stimuli remained effective in evoking prompt decreases in heart rate during periods of apnoea in the end-inspiratory position (Hering-Breuer inflation reflex). In periods of apnoea after prolonged artificial hyperventilation the stimuli were sometimes ineffective at first, but were always effective late in the period of apnoea, again producing prompt cardiac slowing. 5. After denervation of the lungs, brief baroreceptor and chemoreceptor stimuli continued to evoke prompt falls in heart rate when given during expiration. When delivered during inspiration the same stimuli were either ineffective, or less effective.


Voltage-current relationship of a carbachol-induced potassium-ion pathway in Aplysia neurones. 1. The electrical characteristics of a potassium ion selective pathway produced by the action of carbachol on Aplysia neurones (Kehoe, 1972b) has been studied. 2. The relationship between current and voltage has been found to be non-linear, the conductance increasing with depolarization and decreasing with hyperpolarization. The degree of rectification was reduced when the external potassium was raised to 50 mM from its normal value of 10 mM. 3. The direction of the rectification and the effect of increased potassium are as predicted by the 'constant field' theory, but the degree of rectification is somewhat larger.


The interdigestive myo-electric complex of the stomach and small bowel of dogs. 1. Szurszewski (1969) described a cyclic recurring, caudally migrating band of intense action potential activity, the activity fromt, in the small bowel of dogs fasted 18-21 hr. The finding has been confirmed by Carlson, Bedi & Code (1972) and by Grivel & Ruckebusch (1972).  The objectives of the present study were to extend these observations first by indentifying the full sequence of myo-electric events in the stomach and small bowel of healthy conscious dogs fasted for 24-48 hr and for longer periods and second by determining the effect of ingestion of mild and of saline solution on the complex and the role of gastric distension in their action. 2. Under surgical anaesthesia, silver-silver chloride electrodes were implanted on the serosal surface of the stomach and small bowel of seven dogs, and recordings of electric activity were started when the dogs had recovered.  One hundred and nine interdigestive complexes were studied in detail in five of the dogs during period ranging from 5 to 14 months.  All observations were made while the dogs were healthy, conscious, and fasted. 3. The period of intense action potential activity, the activity frot or band, was found to be one phase of a cyclic-recurring sequence of changes in action potential activity.  The entire sequence, composed of four phases, occured almost simultaneously in the stomach and duodenun and then migrated distally in sequence over the entire small bowel.  As one cycle terminated in the distal ileum, another had started in the stomach and duodenum, and this cyclic recurrence continued during fasts of 4 and 5 days. 4. The cycles of the interdigestive complex tended to recur at the same time each day in three of the dogs.  The mean periods of the cycles ranged from 90 to 114 min, and the mean time of their propagation from stomach to terminal ileim ranged from 105 to 134 min.  The mean velocity of the activity fronts (phase III of the cycles) was 5-7-11-7 cm/min in the orad portion of the small bowel and 0-9-2-5 cm/min in the distal half.  The mean calculated length of the activity front diminished from a range of 42-62 cm in the duodenum to 5-10 cm in the ileum. 5. Intragastric instillation of 400 ml. milk always interrupted the complex present in the bowel at the time of instillation and usually suppressed the next, whereas 400 ml. saline solution interrupted the complex present in the bowel only at the time of instillation. Distension of the stomach with a ballon always suppressed the interdigestive complex in the stomach and duodenum but sometimes failed to interrupt its migration along the bowe.


Response of primate cones to sinusoidally flickering homochromatic stimuli. 1. The response of the primate cone photoreceptors to sinusoidally flickering stimuli has been obtained by monitoring the late receptor potential (LRP). 2. By comparing the response characteristics of the foveal local electroretinogram (LERG) before and after the intraocular infusion of sodium aspartate, it was found that the b-wave in the foveal LERG does not affect the monitoring of the LRP to steady-state flicker. 3. Functions describing the supra-threshold frequency response characteristics of the photoreceptors were obtained. 4. Linearity was found to hold for low amplitude responses, and temporal modulation transfer functions (MTFs) were obtained for the photoreceptors at various adaptation levels. 5. The cone photoreceptors were found to act approximately as passive low pass filters compounded with some low frequency attenuation. 6. The high frequency response of the photoreceptors at various adaptation levels tends toward a common high frequency asymptote, much like human psychophysical findings, and can be described by a diffusion model. 7. Non-linearities (convexity-upwards) suggest modest positive feedback at the level of the photoreceptors. 8. Mechanisms limiting the magnitude of the receptor response at low frequencies have little effect on the phase lag of the response.


Linear and non-linear performance of transducer and pupil in Calliphora retinula cells. 1. Intracellular recordings have been made from the blowfly (Calliphora erythrocephala) retinula cell; apart from the transducer mechanism, these cells also feature a pupil mechanism. 2. At several mean intensity levels, within the apparently linear range of response, frequency characteristics of amplitude and phase and responses to 'delta'-flashes and 'delta'-flash pairs have been obtained. 3. Fourier methods have shown these responses to be mutually compatible, confirming linearity in these circumstances. 4. Non-linear behaviour can be made to appear at the lower frequencies when the modulation depth is increased. 5. Non-linearities can also appear through application of the superposition test: a low frequency sine wave, modulated so as to elicit an apparently linear response, and a high frequence sine wave which does not give rise to non-linearity even at the highest modulation depths can, when superimposed, yield a greater response to the latter when situated at the minima of the former than at its maxima. 6. At frequencies above approximately 1 Hz these superposition non-linearities are attributed to the transducer mechanism gain control. Below this frequency the pupil mechanism takes part considerably in the retinula cell's total observed gain control: its characteristics remain yet to be cleared up. 7. The transducer's linear and non-linear properties fit in closely with those of the Fuortes-Hodgkin model which couples increases in gain and time constants. 8. The Fuortes-Hodgkin model will probably require some quantitative modifications in the originally treated case of Limulus, on account of its pupil. 9. Finally, the merits of Veringa's diffusion model, and the possibility of eventually joining this model with the Fuortes-Hodgkin one are pointed out briefly.


Calcium dependent action potentials produced in leech Retzius cells by tetraethylammonium chloride. 1. Retzius cells of leech segmental ganglia were exposed to tetraethylammonium chloride (TEA) presented both extracellularly, dissolved in the perfusing fluid, and intracellulary, by iontophoresis from a microelectrode. 2. Extracellular TEA, 10 and 25 mM, greatly prolonged the cells' action potentials, and the higher concentration increased their amplitude as well. At 10 mM the characteristic changes developed gradually over a period of about half an hour, while at 25 mM they appeared much more rapidly. However, at both concentrations the changes were reversible within minutes, even after long soaks in drug-containing solution. It is therefore probable that the drug acted at the outer surface of the membrane. 3. Intracellular TEA also prolonged the action potentials but there were several differences from the response produced by extracellular application. The changes developed gradually, and for a time, each firing of the cell was a complex event consisting of several early, brief depolarizations followed by a single much larger and more prolonged one. The large, late depolarization eventually obliterated the early ones; its gradual development suggested that it was produced only after TEA diffused to some extrasomatic portion of the cell. Intracellular TEA always caused progressive depolarization; this and the changes in the action potential were both irreversible, suggesting that the site of action was on the inner surface of the membrane. 4. Manipulations of external Na and Ca provided evidence that (a) in the absence of TEA, Retzius cell action potentials were exclusively Na-dependent, (b) that the early depolarizations in the complex action potentials produced by intracellular TEA were Na-dependent, while the later, large depolarization was Ca-dependent and (c) that the prolonged action potentials produced by extracellular TEA contained a large Ca-dependent component. 5. We conclude that TEA, acting from either side of the membrane, caused a voltage-sensitive, slowly activated Ca current to become a major contributor to the inward current of the action potential, probably by blocking the outward K current which ordinarily counteracts it. However, we cannot rule out the possibility that TEA enabled a Ca current by some means independent of its presumed action on K conductance. 6. Data resembling ours in some respects have been obtained from studies of the action of TEA on frog dorsal root ganglion cells, frog neuromuscular junction, and squid stellate ganglion. No clear counterpart of our findings has been reported form experiments on squid and amphibian axons, molluscan neurones, or frog skeletal muscle fibres.


The effects of temperature and 2,4-dinitrophenol on transmembrane potentials of submandibular acinar cells. 1. Micro-electrodes were used to investigate the effect of different temperatures and of DNP on salivary secretory potentials of the cat and the possum produced in response to parasympathetic nerve stimulation. 2. The mean resting potential was unchanged between temperatures of 15 and 40 degrees C in both species. 3. The amplitude of the secretory potential decreased as the temperature was lowered. Below 25 degrees C there was often no response to 1 Hz stimulation but a poorly maintained response to higher frequencies could still be obtained at 20 degrees C. 4. Decrease in temperature prolonged both the latency and time course of the secretory potential. In both species and at all frequencies the latency was increased with a Q10 of about 2-0; the increase in hyperpolarization time had a Q10 of about 1-6. 5. Close arterial injection of DNP (1 times 10- minus 4 M) decreased the amplitude of the parasympathetic secretory potential without affecting its latency and time course or the resting potential. The electrical response to close arterial injection of acetylcholine was also abolished. 6. It was concluded that metabolic energy is required to activate the hyperpolarization mechanism, and this may involve the formation of high-energy phosphate bonds.


Salt-induced changes in sodium transport across the skin of the euryhaline toad, Bufo viridis. 1. Euryhaline toads (Bufo viridis) were adapted to either distilled water, 115 or 200 mM-NaCl solutions. Na transport across the skin of these animals was studied in in vitro preparations. 2. Salinity adaptation caused a reduction in transepithelial potential and short-circuit current across the skin, and increased its electrical resistance. 3. Na influx across the skin was decreased. The reduction accounted fairly well for the measured reduction in short-circuit current. 4. Short-term Na uptake at the outer barrier of the skin was greatly reduced in preparations from salt adapted animals. Amiloride, which usually inhibits Na uptake, did not affect it in skins from salt adapted toads. 5. Sodium conductance decreased by a factor of three in skins from 115 mM-NaCl adapted toads, and to zero in skins from 200 mM-NaCl adapted animals. Shunt conductance was only little affected by the salinity of adaptation. 6. 'Amiloride-sensitive component' of transepithelial Na transport was 55, 21-5, and 4-5 muA/cm-2 in skins from toads which were adapted to distilled water, 115, and 200 mM-NaCl solutions, respectively. 7. It is concluded that the effect of salinity adaptation on the skin of the toad is to reduce the number of Na selective sites at the outer barrier. This change is reflected in a decrease in the 'amiloride-sensitive component' of Na transport across the skin, and could not be increased by aldosterone. Other changes may occur as secondary to that.


The control of retinal ganglion cell discharge by receptive field surrounds. 1. This paper describes the behaviour of the receptive field surround, and how surround signals combine with those from the centre to generate the discharge of the retinal ganglion cells of the cat. 2. A small test spot is flashed upon the middle of the receptive field of an on-centre X-cell, alone, or together with a concentric annulus of fixed luminance. The reduction in discharge brought about by the annulus is independent of spot luminance. From this it is inferred that centre and surround signals combine additively. 3. Knowing that the combination of signals is additive, the surround signal can be estimated by comparing the ganglion cell's response to diffuse illumination of its receptive field with that to an equiluminous spot which optimally stimulates the centre while encroaching minimally upon the periphery. 4. Application of this technique to X-cells shows that although the surround seems to have a threshold, it is at its most sensitive in the dark-adapted eye, and typically is only 0.3-0.5 log units less sensitive than the centre. 5. Centre and surround sensitivities are decreased from their dark-adapted levels by increasing background illumination, but the decline of surround sensitivity is initially less rapid than that of the centre. Thus with increasing light-adaptation the surround becomes relatively more sensitive. In the light-adapted eye centre and surround are about equally sensitive to diffuse illumination. 6. Although, in the dark-adapted eye, illumination of the receptive field periphery of an on-centre unit depresses firing, removal of that illumination produces no off-discharge. Off-discharges appear only when background illumination exceeds about 104 quanta (507)/deg 2 sec. This confirms Barlow & Levick (1969b). 7. In the dark-adapted eye surround latency is longer than that of the centre. With increasing background illumination the latency difference is reduced. 8. For X-cells, the rate of the maintained discharge depends to some extent on the balance of centre-surround antagonism. But this antagonism is not the major factor accounting for the relative constancy of mean rate at high background luminances, for the rate then can be almost independent of the size of a steady pot. 9. The mean rate of discharge of Y-cells seems to depend even less upon the balance of centre-surround antagonism. 10. Y-cell surrounds could not properly be isolated with the optimal spot-diffuse illumination technique, so detailed measurements of their behaviour were not made. However, the dark-adapted surround appear to be as sensitive as those of X-cells.


Surround contribution to light adaptation in cat retinal ganglion cells. 1. The sensitivity of a cat's retinal ganglion cell to a small, dim, spot flashed upon the middle of the receptive field depends upon the size of a concentric steady background: sensitivity is reduced monotonically with background area. All backgrounds which equal or exceed in size the central summing area of the ganglion cell produce an equivalent reduction of sensitivity, even though only backgrounds which extend outside the central summing area depress the maintained discharge. 2. If a small background lies upon the middle of the receptive field, and the test spot is made intense enough to evoke a strong response, steady illumination of the periphery may make the response larger. 3. This change in response is not due to an enhancement of centre sensitivity by the surround, but is readily understood if steady illumination of the periphery adapts out the surround's antagonism of the centre's response to the test flash. 4. The failure of steady stimulation of the surround to alter centre sensitivity implies that signals from the surround subtract from, or add to, those from the centre.


Contrast sensitivity in humans with abnormal visual experience. 1. Grating contrast sensitivities have been determined over a range of spatial frequencies for a normal subject and for subjects who are visually biased in that they have a lower resolution capacity for targets of specific orientations. The bias si only found in astigmatic subjects and the grating orientation yielding poorest acuity coincides with the most defocused astigmatic meridian. However this resolution anisotropy remains when optical factors are accounted for. 2. For the normal subject, high and low frequency attenuation is found and a typical reduction in contrast sensitivity is exhibited for oblique target orientations. 3. The biased subjects, called meridional amblyopes because they  have reduced acuity for a given grating orientation, show markedly abnormal contrast sensitivity functions. Their cut-off spatial frequencies are different for various target orientations and this difference applies also to contrast sensitivity over nearly the entire spatial frequency range tested (0-5-16 cycles/deg). The differences are of about the same magnitude for most frequencies and they are found in all types of meridional amblyopes. 4. Optical explanations of these differences are ruled out by laser-interference fringe tests and by varying effective pupil size. 5. Theoretical effects of defocus have been calculated to compare predicted visual deprivation with performance. Results indicate that reduced contrast sensitivity functions can be equivalent to a small defocus effect. 6. To examine the results in the spatial domain, inverse Fourier transforms of representative contrast sensitivity functions have been computed. The optical portion of the resulting spatial weighting functions has been parcelled out to obtain neural spatial weighting functions.


Visual evoked responses in humans with abnormal visual experience. 1. The visual evoked response to a grating target of varying spatial frequency was examined for normal subjects and for subjects with meridional amblyopia. This condition, reduced visual resolution for specific target orientations, is associated with, and thought to result from, marked ocular astigmatism. 2. For normal subjects, the general relation between spatial frequency and the evoked response is similar to psychophysical contrast sensitivity data. Evoked response amplitudes to oblique gratings are typically reduced and this is analogous to the lower acuity for oblique compared to horizontal and vertical detail. 3. In addition to the oblique effect, the magnitude of the evoked response for meridional amblyopes depends upon grating orientation over most of the spatial frequency range tested (0-5-16 cycles/deg). The lowest evoked amplitude is found when stimulus grating orientation matches that for which acuity is reduced. 4. The evoked potentials spatial frequency response functions are qualitatively similar to contrast sensitivity functions determined with the same abnormal subjects. 5. From these results, it may be concluded that the physiological locus of meridional amblyopia is confined primarily to structures at or prior to the site of evoked potential generation.


The interaction between foreign and original motor nerves innervating the soleus muscle of rats. 1. The fibular nerve was transplanted on to the soleus muscle of the rats. Interruption of the original soleus nerve then permitted cross-innervation, and subsequently, over a period of weeks, re-innervation by the original nerve. 2. Individual muscle fibres were often innervated by both the original and the foreign nerve. The original and foreign end-plates were located in separate regions of the muscle. There were no indications that the original nerve could displace or repress the foreign innervation. 3. The extent of re-innervation by the original nerve depended upon the method of denervation. A single crush of the nerve was followed by virtually complete re-innervation, even of muscle fibres already innervated by the foreign nerve. When re-innervation was delayed by resection of a segment of the nerve only muscle fibres without foreign nerve innervation were re-innervated. Denervation by a simple nerve cut gave an intermediate result. 4. Re-innervation by the original nerve can take place without measurable extrajunctional sensitivity to ACh. 5. The original end-plate region could retain high and localized sensitivity to ACh for several months despite degeneration of its motor nerve terminal and activity of the muscle fibre. 6. Established foreign end-plates were re-innervated by the foreign nerve on muscle fibres with intact original innervation. 7. The factors controlling synapse formation in skeletal muscles are discussed.


Corticofugal effects from sensorimotor area I and somatosensory area II on neurones of the pontine nuclei in the cat. 1. The objective of the present experiments was to study the cortical influence from sensorimotor area I (SM I) and from somatosensory area II (S II) on single neurones of the pontine nuclei (PN) in cats under N2--thiamylal anaesthesia. 2. Extracellular single unit recordings revealed a considerable convergence from S II and SM I. Out of ninety-one PN neurones (identified as ponto-cerebellas neurones by antidromic stimulation of the contralateral brachium pontis), fifty-seven neurones were influenced by stimulation of at least one cortical site. Slightly less than half of these neurones (twenty-five) had a convergent input from SM I and S II; twenty-three PN neurones were excited by SM I only and nine PN neurones by S II only. The proportion of PN neurones excited via collaterals of cortico-spinal neurones was small and restricted to those neurones which had an input from SM I. 3. Sixty per cent of the ponto-cerebellar neurones were reliably activated by natural stimulation such as tapping or passive manipulations of limbs of various joints. The vast majority (thirty-three out of thirty-six PN neurones) which had receptive fields were also influenced by electrical stimulation of one or both cortical areas. The long latency and low probability of discharge to peripheral nerve stimulation suggest a complex, probably transcortical, pathway from the periphery to the PN. 4. The distribution of latencies to both cortical and brachium pontis stimulation indicates that the PN are a relay for fast and slow cerebro-cerebellar connexions. 5. The convergence from cortical areas on PN indicates that the neurones influenced from somatic areas SM I and S II transmit integrated patterns of activity to the cerebellum.


Oral stereognosis: effect of varying form set, answer type, and retention time. The oral stereognosis abilities of 40 young adults were investigated as a function of oral stereognosis form sets (four sets), retention time (unlimited and 5 sec), and response type (oral discrimination and visual recognition). Results showed that the Penn State forms were the easiest for the subjects under all conditions and that the Ringel form set was the most difficult under all conditions. A significant interaction between oral form sets and answer type indicated that the visual recognition task, rather than the discrimination task, was primarily responsible for the differences between the oral form sets. A three-way interaction revealed that the retention times had a significant effect on the two form sets of medium difficulty (NIDR-10 and NIDR-20) for the visual recognition condition. The results are discussed in view of their research and clinical implications.


Hormonal regulation of proteins in the uterine secretion of ovariectomized rats and the implications for implantation and embryonic diapause. Uterine secretions were obtained from long-term ovariectomized rats given progesterone for 10 days followed by oestrogen and progesterone. Analysis of the protein content was carried out using polyacrylamide disc gel electrophoresis at pH8-9 AND ALSO OF THE PROTEIN-SODIUM DODECYL SULPHATE COMPLEXES. When progesterone was given alone, there was a lack of high molecular weight proteins. When oestradiol was also given, a protein (mol. wt 70,000) was detected within 1 hr. At 13 to 20 hr after oestrogen, there was a shift towards the secretion of high molecular weight proteins when the secretion profiles were similar to those of normal pregnant animals at Day 5, the day of implantation in the rat. The hormonal regulation of the secretion proteins is discussed. The physiological aspects of implantation in terms of zona lysis, embryonic diapause and the release from diapause after oestrogen treatment are discussed with reference to the changes in the intraluminal proteins.


Fertilization of rat eggs in vitro at various times before and after ovulation with special reference to fertilization of ovarian oocytes matured in culture. Oocytes recovered at various times from immature rats treated with PMSG and HCG were incubated with capacitated epididymal spermatozoa of mature rats. In the presence of follicular cells, sperm penetration was not observed 4 hr after incubation in the oocytes at stages from the intact germinal vesicle to the chromatin mass, but 7 to 55% of oocytes were penetrated at stages from the condensed germainal vesicle to metaphase II. After the removal of follicular cells, 15 to 72% of the oocytes at any stage were penetrated. After further incubation for 15 hr, the proportion of penetrated oocytes increased from 8 to 98% from early to late stages and that of penetrated oocytes with a male and female pronucleus increased from 9 to 100% as maturation progressed. Although the average number of spermatozoa/oocyte was not correlated with its maturation, transformation of the sperm head into a male pronucleus was retarded or failed, especially in the younger oocytes. Following incubation in a defined medium for 13 hr, 85% of oocytes at the intact germinal vesicle stage matured to the stage of the first polar body formation, but only 18 to 22% of these mature oocytes were penetrated by spermatozoa and only a few of the penetrated oocytes cleaved into normal two-cell eggs. When eggs recovered from oviducts 14 to 20 hr after ovulation were exposed to capacitated spermatozoa, the proportion of penetrated eggs (86 to 98%) and that of polyspermic eggs (11 to 27%) were not related to the ages of the eggs, but failure of transformation of the sperm head and the proportion of abnormal eggs increased 14 to 20 hr after ovulation.


Lactogenesis in the rat: an ultrastructural study of the initiation of the secretory process. Three specimens were taken from mammary glands of rats killed on the 18th and 21st days of pregnancy and on the 1st day of lactation. Ultrastructural features of the tissue were compared among rats within and between the two stages of development. The similarity among specimens from the same rats made feasible a comparison of serial biopsies obtained every 4 hr, starting on the afternoon of the 21st day of pregnancy. From the 18th to the 21st days of pregnancy, a marked increase in the amount of rough endoplasmic reticulum occurred. The alveolar cells of rats killed on both days and in biopsies obtained at 17 and 13 hr before partuirtion contained abundant small lipid droplets and vacuoles containing many protein granules with little clear fluid (stasis vacuoles). Alveolar lumina were distended with secretion by 17 hr before parturition. Between 8 and 12 hr. before parturition, the accumulated protein and lipid were rapidly extruded from the alveolar cells despite evidence of continued biosynthesis. It is suggested that active transport processes are initiated independently of milk synthesis before parturition.


An ultrastructural study of the reversibility of the effects of hypoxia on human trophoblast maintained in organ culture. Ultrastructural changes in normal human trophoblast maintained in hypoxic organ culture are described. Marked structural changes were noted even after hypoxia for 6 hr. These changes could be partly reversed by reoxygenation after hypoxia for 18 hr or less, but no regeneration occurred when hypoxia lasted for 24 hr or longer. The significance of the vulnerability of trophoblast to hypoxia is discussed.